Nice neighborhood: emerging concepts of the stem cell niche

Abstract

No metazoan cell survives on its own, absent the signals and support of its milieu. For multicellular life with specialized tissues to persist, organization is everything and so defining the association of position with cell state is critical to understanding how tissues function, maintain, and repair. This review focuses specifically on place for progenitor and stem cells. Especially emphasized are hematopoietic cells that balance free movement and stable position and where concepts of regulatory interrelationships have been shown with some precision. It reviews classical and emerging concepts of the niche, particularly considering how niche functions may participate in neoplastic disease.

Figure 1. Elements of a stem cell niche as originally proposed by Raymond Schofield

Image of Schofield provided by his colleague Brian Lord. Note the background drawing of the blind men and the elephant parable: an appropriate cautionary reminder of the need for integration of partial information for full understanding of niche biology.

Figure 2. Niche effects on inhabitant diversity from ecologic models

Settings of stable environmental conditions enable dominance of a competitively advantaged population to the progressive exclusion of less fit populations (left). However, in the context of increased variability of niche conditions, the number of subpopulations supported in a given microenvironment increases resulting in a greater diversity of inhabitants (right).

Figure 3. How population dynamics of stromal support populations may influence the relative likelihood of contributing to a neoplastic outgrowth

Abnormal hematopoietic subpopulations that depend upon stromal support will persist provided there is a ‘match’ between the supportive context the stroma provides and the needs of the mutant hematopoietic stem/progenitor cells. The likelihood such cooperating pairing will occur is low if the stromal cells rarely turnover or are replenished by mature cell division (left). In such a setting, the abnormal hematopoietic cell may be lost by competitive exclusion. However, if stromal cells are dynamic with frequent cell replenishment occurring by production of mature stromal cells from stem cells, then a cooperating alteration in a stromal ‘field’ supporting abnormal hematopoietic populations would be more likely to occur and the abnormal clone to persist (right).

Figure 4. Dynamics of genetic changes in the stem cell niche

Diversity of subpopulations introduced by accumulating genetic changes may increase over time in both the support and supported cells leading to an increased likelihood of cooperation between cell types to enable neoplasia.

Figure 5. Niche as an interlocutor of organismal needs

How the niche must incorporate signals indicating the state of the tissue and organism to properly regulate cell production under homeostatic and stress conditions.